Beta-phenyl-beta-pyridyl and beta-phenyl-beta-piperidyl ethyl amines



Patented May 16, 1950 UNITED STATES TENT OFFICE s-rHENYL-s-PmmYL AND,G-PHENYL fi- PIPERIDYL ,ETHYL AMINES Max Hartmann and Leandro Panizzon,Riehen, Switzerlandassignors to Ciba Pharmaceutical Products 'Inc.,Summit, N. J., a cforporaticn of New Jersey No Drawing. Originalapplication March 9, 1945,

Serial No.- 581,97'1. "Divided and this applicationDecember '26, 1946,SeriaTNo. 718,631. In

Switzerland January 19, 1944.

Sectionl,.PublicLaw'690, August 8, 1946 Patent expires January 19, 1964monoarylaceto-nitriles whose acetonitrile radical contains at least onehydrogen atom to react with nuclear halogenated pyridines andpiperidines in the presence of agents eliminating hydrogen halide, ifdesired, replacing one hydrogen atom at' the carbon atom linked to thenitrile group by an alkyl radical, transforming the nitrile group in thecompounds thus obtained into a methyleneamino group in one or severalsteps, if desired, converting the resulting pyr idines into thecorresponding piperidines 'by means of reducing agents and/or, ifdesired, further substituting the pyridine or piperidine compounds thusobtained at the ring nitrogenatom.

The monoaryl-acetonitriles used for the reaction may contain asubstituent in the methylene group of theacetonitrile radical and one ofseveral substituents in the 'aryl radical. are:-pheny1 acetonitrile,naphthyl acetonitrile, a-phenyl-a-alkyl-acetonitriles, such as a. phenyla methyl-acetonitrile, 3'-methoxyphenyl-acetonitrile, 3:4-dimethoxyp'henyl-acetonitrile, 3:4-methylene-dioxyphenyl-acetonitrile. Nuclear halogenated pyridines andpiperidines are for example:-2-ch1oro-pyridine, i-chloropyridine,1-methyl-3-chloro-piperidine. These may also contain furthersubstituents. Thus 2-chloro-5-nitro-pyridine may be used as start- Thereaction is carried out pref-- ing material. erably in inert solvents,such as for example ether, benzene, toluene and the like. For theelimination of the hydrogen halide there are preferably used sodium,potassium, lithium as such or in the form of their amides, hydrides,alcoholates or hydrocarbon compounds, such as for example sodium amide,sodium hydride, potassium tertiary butylate; potassium tertiary amylate,butyl-lithium, phenyl-sodium or phenyllithium.

If acetonitriles are obtained in this reaction which still contain ahydrogen atom at the carbon atom linked with the nitrile group, this canbe replaced by the corresponding alkyl radicals, for example by reactionwith alkyl halides, such as methyl, ethyl or diethylaminoethyl chloridein the presence of agents eliminating hydrogen halide.

Examples For the purpose of producing the amines the nitriles aretreated with reducing agents. When using u-aryl-apyridy1-acetonitriles,the reaction, by suitable selection of the reducing agents andconditions, can be conducted in such a manner that there are formedeither fi-aryl-B-pyridylethylamines or p-aryl-p-piperidyl-ethylamines.

In this reduction of the 'nitril'es to the amines also secondary basesare formed, besides primary bases, depending on the conditions applied.13- phenyl fl -,pyridyl (2) ethyla'mine and (ii-(18-p'henyl-fi-pyridyl-(Z) ethyh-amine are thus obtained for example fromcz-DhGllYl-a-DYlidYl- (2) -'acetonitrile in an alcohol solution withhydrogen in the presence of nickel catalyst at a low temperature. Theresulting primary and secondary ethylamines can be further substitutedin the amino group acc'ording'to the usual meth-' eds.

The pyridylethylamines obtained according to the present process can beconverted into the cor J aryl-sulfonic acidesters, cliailkyl-sulfates oralso arylalkyl-halides. It is also-possible to obtain tertiarypiperidines by starting from piperidines which are not substituted :atthe ring nitrogen atom.

The compounds produced according to the present process possess valuablephysiological properties and may be used as medicamentsor asintermediateproducts for the preparation of medicaments.

"The following examples illustrate the invention, but are not to beregarded as limiting it in anyway:-

Example 1 :grams of pulverizedi sodium amide are graduallyj'added,whil-estirring and cooling, to a solution of 11'? g. ofphenyhaeetonitrile and 113 g. of Z-chIorOpyridine in 400 cc. of absolutetoluene. The mixture is then slowly heated to ll.0-

C. and maintained at this temperature for 1;

hour. Water is added thereto after cooling, the toluene solution isshaken with dilute hydrochloric acid and the hydrochloric acid extractsare made alkaline with concentrated caustic soda solution. A solid massis separated thereby which is taken up in ethyl acetate and distilled,wphenyl-a-pyridyl-(2) -acetonitrile passing over at 150-155 C. under 0.5mm. pressure. When recrystallized from ethyl acetate it melts at 8889C., the yield amounting to 135 g.

In similar manner there are obtained a-(3- methoxyphenyl) apyridy1-(2)-acetonitrile of melting point 54-55 C. when starting from 3-methoxyphenyl-acetonitrile and 2-chloropyridine, a-(3:4-dimethoxyphenyl) a pyridyl-(2) acetonitrile of boiling point192-195 C. under 0.2 mm. pressure when starting from3:4-dimethoXy-phenyl-acetonitrile and Z-chloropyridine, a- (3:4methylene dioxy phenyl) -a-pyridyl-(2)-acetonitrile of boiling point170-180" C. under 0.15 mm. pressure when starting from3:4-methylene-dioxyphenyl-acetonitrile and 2- chloropyridine,a-naphthyl-(l) a pyridyl-(2) acetonitrile of melting point 87 C. whenstarting from naphthyl-(l)-acetonitrile and 2-chloropyridine,a-phenyl-e-methyl a pyridyl- (2) acetonitrile of boiling point 145-150C. under 0.2 mm. pressure when starting from a-phenyl--e-methylacetonitrile and 2-chloropyridine, phenyl-a-pyridyl (4)acetonitrile of melting point 76-77 C. when starting fromphenylacetonitrile and 4-chloropyridine, a-IDhGIlYl-aethyla-pyridyl-(4)-acetonitrile of boiling point 193 C. under 11 mm. pressure whenstarting from a-phenyl-a-ethyl-acetonitrile and 4-chloropyridine, anda-phenyl-e-[N-methyl-piperidyl- (3)1-acetonitri1e of boiling point140-145 C. under 0.2 mm. pressure when starting from phenyl-acetonitrileand N-methyl 3 chloropiperidine.

The indicated a-phenyl a alkyl a pyridylacetonitriles can also beobtained by alkylation of a-phenyl-a-pyridyl-acetonitrile with thecorresponding alkyl-halides in the presence of sodium amide.

Example 2 20 g. of the a-phenyI-u-pyridyI-(Z)-acetonitrile described inExample 1 are dissolved in 150 cc. of absolute ethyl alcohol and reducedat 60-70 C. in an autoclave with hydrogen in presence of 5 g. of nickelcatalyst. After the quantity of hydrogen (4 atoms) calculated for thereduction of the CN group has been taken up, the decrease of pressureceases. After suction-filtering the catalyst and evaporating thesolution there is obtained an oily substance from which by mixing itwith 200 cc. of ethyl acetate and 4 cc. of glacial acetic acid g. of

-the acetate of the primary base B-phenyl-flpyridyl- (2) ethylamine canbe precipitated. The acetate melts at 124 C. and the base which has beenliberated therefrom boils at 130 C. under a pressure of 0.15 mm. Thehydrochloride melts at 210-211 C. The ethyl acetate filtrate isevaporated, the residue is mixed with caustic alkali solution and takenup in ether. The ether residue consists of about 10 grams of the crudesecondary base di- [[3 phenyl B pyridyl-(2) ethyll-amine; it melts at84-85 C. when recrystallized from ether, the hydrobrcmide melts at 140C.and the picrate at 179-180 C.

The following amines are prepared in analogous manner: froma-(3-methoxyphenyl)-a-pyridyl-(2) -acetonitrile the B- (3-methoxyphenyl)4 flpyridy1(2)-ethylamine as hydrochloride of melting point 210211 C.and the di- [fi-3-methoxyphenyl) -l yridyl-(2)-ethyl]-amine as picrateof melting point C.; and from a-phenyla-pyridyl-(4)-acetonitri1e thefl-phenyl-fl-pyridyl-(4)-ethylamine as hydrochloride of melting point199 C. and the di-[fi-phenyl-B-pyridyl-(4)-ethyll-amine as picrate ofmelting point 187 C.

The formation of the primary bases can be favored by hydrogenation ofthe nitriles in the presence of ammonia. For example there are obtained:p-phenyl-B-pyridyl- (4) -B-ethylamine of flooiling point 130-135 C.under 0.2 mm. pressure, fi-naphthyl- 1) -B-pyridyl- (2) -ethylamine andfi-methylene-dioxyphenyl ,3 pyridyl-(2) ethylamine.

For example the following derivatives can be prepared from the foregoingamines: from 6- phenyl-B-pyridyl-(Z) -ethy1amine by hydrogenation withhydrogen in the presence of platinum catalyst the p-phenyl-p-piperidyl(2) ethylamine as acetate of melting point 99 C. and the di[fi-phenyl-fi-piperidyl-(2) -ethyl]-amine of melting point 82 C., bycondensation with formaldehyde in the presence of formic acid the,9-phenyl 8 pyridyl (2) ethyl-dimethylamine, as hydrochloride of meltingpoint C., by condensation with 1 mol. of formaldehyde and hydrogenationof the resulting Schifis base and of the pyridine nucleus with hydrogenin the presence of a platinum catalyst the B-phenyl- 5-piperidyl-(2)-ethyl-monomethylamine of boiling point 147-152 C. under. 0.1 mm.pressure, by condensation with benzaldehyde and hydrogenation at 20 C.the p-phenyl-p-pyridyl-(2)- ethyl-benzylamine, by condensation withbenzaldehyde and hydrogenation at 60-70 C. the 5- phenyl B piperidyl-(Z)-ethyl-benzylamine, by condensation with pyridyl-(3)-aldehyde andhydrogenation of the Schiffs base the B-phenyl- B pyridyl (2) ethyl[pyridyl (3) methyl]- amine of boiling point 190-195 C. under 0.25

mm. pressure, by reaction with cyanamide the p-phenyl-B-pyrldyl-(2)-ethyl-guanidine as acetate of melting point 202 C. and thecorresponding derivatives from other amines.

Having thus disclosed the invention, what is claimed is:

1. A compound of the formula 2: R1 Ar(JOH;-N

I Fe B:

wherein Ar stands for a member selected from the group consisting ofmonocyclic aryl and condensed bicyclic aryl, X stands for a memberselected from the group consisting of hydrogen and lower alkyl, Pestands for a member selected from the group consisting of pyridine andpiperidine radicals, a carbon atom of which is directly connected withC, and

stands for a member selected from the group consisting of amino, loweralkylamino, lower dialkylamino, lower aralkylamino, pyridylamino andCHa-( IJAr 5 wherein Ar, X and Pe have the precedingly-re- REFERENCESQITIED cited slgmficances' The foilowing references are of record in the2. A primary p-phenyl-p-pyrldyl-ethylam1ne. file of this patent: 3. Aprimary li-phenyl-fi-pyridyl-Q) -ethy1- amine 5 FOREIGN PATENTS 4. The5-pheny1-B-pyridy1-(2)-ethy1amine. Number Country Date 5.Di-[fi-phenyl-fi-pyridyl-ethyl]-amine. 309,300 Great Britain Apr. 11,'1929 6. 7. The (211- [,B-phenyl B pyridyl -(2) ethyll- O R ER CES amine1n Rupe et a1., Helv. Chim. Acta 8338-340 (1925) 8. A primary5-pheny1-Bpiperidy1-ethy1amine. Journal of the American ChemicalSociety, vol.

9. A rimar hen 1- i erid 1-(2)-eth 66 (1944)pp' 725-731) p y 5 p y B p py yl Chemical Abstracts 40, 3117 (1946).

a h 1 j id 1..(2) ethy1amine Hartman, California and Western Medicine 6611. Di-[l3-pheny1-B-piperidyl-ethy11-amine. 4) y 12. Di [[3 phenyl [1?piperidyl t sidgwlck, Orgamc Chemistry of Nitrogen, page amine.

13. The (11- [/i-phenyl-fl-piperidyl- (2) -ethy1] amine.

MAX HARTMANN. 20 LEAN DRO PAN IZZON.

1. A COMPOUND OF THE FORMULA